Technological advances of molecular biology are posed to bring new methods of diagnosis and treatment to clinical practice. Among other things these methods should improve on the sensitivity of existing techniques, be sufficiently robust to allow multi-parametric evaluation of clinical samples, and should not require invasive procedures for sample acquisition. In this proposal we will test a combination of existing modern techniques, which is designed to provide high-throughput, multi- parametric detection of diffuse large B-cell lymphoma. In R21 phase of the project we will use cultured cell and paraffin-embedded tissues of patients to determine sensitivity, selectivity and variability of the assay. When the milestones of R21 phase are met we will move into clinical R33 phase of the project, testing the assay's ability to detect lymphoma- specific DNA in patient's plasma. We will test correlation of the assay's results with clinical diagnosis of diffuse large B-cell lymphoma, and with clinical outcomes, including disease-free survival and drug resistence. When the assay is optimized for disease detection in patient's plasma we will also address the issue of residual disease detection and monitoring of treatment efficacy.